swan, d., cullen, w., macias, j., oprea, c., story, a ... · 1 title: hepcare europe - bridging the...
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Swan, D., Cullen, W., Macias, J., Oprea, C., Story, A., Surey, J., ... Lambert,J. S. (2018). Hepcare Europe - bridging the gap in the treatment of hepatitisC: study protocol. Expert Review of Gastroenterology and Hepatology,12(3), 303-314. https://doi.org/10.1080/17474124.2018.1424541
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TITLE: Hepcare Europe - Bridging the gap in the treatment of Hepatitis C: Study Protocol
AUTHORS: Davina Swan, Walter Cullen, Juan Macias, Cristiana Oprea, Alistair Story,
Julian Surey, Peter Vickerman, John S. Lambert.
AFFILIATIONS:
Davina Swan, UCD School of Medicine, University College Dublin, Belfield, Dublin 4,
Ireland. Email: [email protected]
Walter Cullen, UCD School of Medicine, University College Dublin, Belfield, Dublin 4,
Ireland. Email: [email protected]
Juan Macias, Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario
de Valme, Seville, Spain. Email: [email protected]
Cristiana Oprea, Victor Babes Clinical Hospital for Infectious and Tropical Diseases,
Bucharest, Romania; and Carol Davila University of Medicine and Pharmacy, Bucharest,
Romania. Email: [email protected]
Alistair Story, Find and Treat, NHS, London, UK. Email: [email protected]
Julian Surey, Institute of Global Health, University College London, UK. Email:
Peter Vickerman, School of Social and Community Medicine, Oakfield House, University of
Bristol, Bristol, UK. Email: [email protected]
John S. Lambert, Centre for Research in Infectious Diseases, Mater Misericordiae University
Hospital, Dublin 7, Ireland; and UCD School of Medicine, University College Dublin,
Belfield, Dublin 4, Ireland. Email: [email protected]
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CORRESPONDING AUTHOR:
Name: Dr John S. Lambert
Address: Catherine McAuley Education & Research Centre, 21 Nelson Street, Dublin 7,
Ireland.
Email: [email protected]
Telephone: +353 (0)1 7164530
Fax: +353 (0)1 7164535
Acknowledgements:
This project is funded by the European Commission through its EU Third Health Programme
(Grant Agreement Number 709844) and Ireland’s Health Services Executive. PV was
additionally supported by the National Institute for Drug Abuse [grant number R01
DA037773-01A1], and acknowledges support from the National Institute of Health Research
Health Protection Research Unit in Evaluation of Interventions.
We thank our colleagues, Ms Suzanne Barror and Dr Geoff McCombe (School of Medicine,
UCD) for their helpful comments and feedback on earlier drafts of the manuscript.
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TITLE: Hepcare Europe - Bridging the gap in the treatment of Hepatitis C: Study Protocol
ABSTRACT:
Background. Hepatitis C (HCV) infection is highly prevalent among people who inject drugs
(PWID). Many PWID are unaware of their infection and few have received HCV treatment.
Recent developments in treatment offer cure rates >90%. However, the potential of these
treatments will only be realised if HCV identification among PWID with linkage to treatment
is optimised. This paper describes the Hepcare Europe project, a collaboration between five
institutions across four member states (Ireland, UK, Spain, Romania), to develop, implement
and evaluate interventions to improve the identification, evaluation and treatment of HCV
among PWID.
Research design and methods. A service innovation project and a mixed-methods, pre-post
intervention study, Hepcare will design and deliver interventions in Dublin, London, Seville
and Bucharest to enhance PWID engagement and retention in the cascade of HCV care. The
feasibility, acceptability, potential efficacy and cost-effectiveness of these interventions to
improve care processes and outcomes among PWID will be evaluated.
Conclusions. Hepcare has the potential to make an important impact on patient care for
marginalised populations who might otherwise go undiagnosed and untreated. Lessons
learned from the study can be incorporated into national and European guidelines and
strategies for HCV.
KEYWORDS: Hepatitis C, HCV, PWID, homeless, prisoners, screening, linkage to care,
treatment, interventions, Europe
1. BACKGROUND
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In the European Union (EU) and European Economic Area (EEA), approximately 5.6 million
people have been infected with the Hepatitis C Virus (HCV) (1.1% of the general
population). However, national estimates of seroprevalence vary widely, from 0.1% in
Belgium, Ireland and the Netherlands to 5.9% in Italy (1). Approximately 50-80% of
individuals infected with HCV will develop chronic infection which is associated with liver
cirrhosis and hepatocellular carcinoma (HCC) (2, 3).
People who inject drugs (PWID) and ex-PWID bear the greatest burden of HCV infection in
Europe and account for the majority of new infections. Estimates suggest that of 1.2 million
current PWID in the EU/EFTA area, 0.7 million have been infected with HCV and 0.5
million are chronically infected (4). Prevalence varies substantially between countries:
according to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA),
HCV antibody (anti-HCV) prevalence among national samples of PWID in 2014–15 ranged
from 16%-84% (5). Modelling studies predict substantial increases in liver disease among
ageing HCV-infected PWID populations (6, 7).
Despite the high prevalence of HCV among PWID, many are unaware of their infection and
few have received treatment. Estimates of undiagnosed infection among PWID in Europe
range from 24%-76% (8). Among PWID diagnosed with chronic hepatitis C (CHC), the
proportion entering HCV treatment is low (range 1–19%) (8). Low treatment rates are in part
explained by the suboptimal referral of PWID post-diagnosis to specialist secondary care for
evaluation and treatment of HCV (9), and also by poor attendance and defection from
secondary care among those who are referred (10).
5
The World Health Organization’s (WHO) recently developed Global Health Sector Strategy
(GHSS) on viral hepatitis aims to eliminate viral hepatitis as a major public health threat,
including the following targets for 2030 (11):
Reduce CHC incidence by 90%;
Reduce HCV-related mortality by 65%;
Diagnose 90% of CHC infections;
Treat 80% of eligible persons with CHC.
To achieve these targets, it is essential that countries increase prevention, testing and linkage
of diagnosed individuals to treatment. As many PWID remain unaware of their infection
and/or are not accessing HCV care, it is evident that new strategies to reach such individuals
are necessary, including new testing strategies to increase the number diagnosed, and
improved care pathways to ensure those diagnosed are successfully linked to HCV evaluation
and treatment.
Previous research has identified a range of barriers to PWID accessing HCV screening,
evaluation and treatment, including: anticipated stigma and discrimination, restrictions
around HCV treatment eligibility, inconvenience of travelling to testing sites and hospitals,
fear of HCV investigations and treatment side-effects, perceptions of HCV as relatively
benign, being asymptomatic, and competing priorities (12, 13). Further barriers are a low
level of awareness and HCV literacy among patients, healthcare providers, policy-makers,
and the general public and limited attention, resources and commitment to HCV care at the
political level (14).
Recent developments in HCV diagnostics and treatment can enhance access to, and uptake
of, HCV care among PWID. Recently licensed point of care tests (POCTs) for HCV,
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including rapid diagnostic tests (RDTs) from finger prick blood samples and oral secretions,
are portable, easy to use and often less invasive than traditional venous blood sampling. Thus,
they have the potential to make HCV diagnosis more available for many populations by
facilitating outreach of screening beyond clinical settings and personnel. As most POCTs
provide a result within 5-30 minutes (15), they may also enhance retention of patients in the
subsequent cascade of HCV care.
Likewise, the replacement of liver biopsy by transient elastography (FibroScanTM, Echosens,
Paris), for the staging of liver fibrosis, enhances opportunities for the extension of specialist
evaluation of HCV disease from hospital into community settings to reach more patients. In
addition to being non-invasive, the FibroScan has advantages, including: (i) being portable, it
can be transported to community sites to assess patients; (ii) individuals can relatively easily
be trained in its use; and (iii) scans can be conducted within less than five minutes and results
given immediately to patients, which may enhance their engagement with HCV treatment as
previous studies have shown how clinical markers can impact patients’ perceptions of HCV
disease (12, 16).
However, the revolution in HCV treatment is the most significant advance in HCV care. The
replacement of pegylated interferon and ribavirin with new interferon-free direct acting
antiviral agents (DAAs) has reduced HCV treatment times to 8-12 weeks, improved safety
profiles, and increased cure rates to >90% of cases (17, 18). These relatively simple, tolerable
and highly effective treatments are improving treatment uptake among patients and
enhancing opportunities for provision of treatment in community settings (19).
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These developments in treatment make HCV elimination among PWID feasible (14).
Modelling studies have shown that if treatment is delivered at the right scale, it can have a
major preventative impact on HCV transmission (20). A challenge is the current high cost of
the DAA treatments, which is a barrier even for high-income countries to deliver treatment at
the scale needed. If price reform is not achieved, this could undermine countries efforts to
impact upon the growing liver disease burden (21). However, even if DAA treatments were
affordable and accessible to all, the full clinical impact of these therapies will be contingent
on engaging and retaining PWID in the HCV cascade of care (22).
Attention now needs to turn to developing evidence-based, culturally appropriate strategies to
improve diagnosis and linkage to care of PWID (14, 22). Several authors have argued that to
optimise the potential of the new HCV therapies when they become more widely available,
now is the time to scale up prevention, educate patients and healthcare providers, and identify
the best interventions to enhance delivery of screening, assessment and treatment (14, 23).
A recent systematic review and meta-analysis of operational interventions to improve
engagement and retention along the HCV cascade of care identified some effective strategies
(22), including: reminders to clinicians regarding testing, HCV education and pre-test
counselling accompanied by on-site testing, facilitated referral to specialist care, integration
of mental health and substance misuse management with HCV treatment services, and nurse-
led educational sessions about HCV treatment. This review did not restrict studies to PWID,
although most studies were conducted amongst this population. A more recent systematic
review which focused on PWID, people who use drugs and OST populations arrived at
similar conclusions, including the effectiveness of dried blood spot (DBS) testing to enhance
testing uptake (24). HCV treatment in almost all studies within both reviews was interferon-
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based. Both reviews concluded that many of the studies were of low quality and further
operational research is needed to optimise hepatitis care services (22, 24). The design and
evaluation of interventions which simplify the HCV cascade of care in the new DAA
treatment era, and which target multiple components within the care cascade, was identified
as a research priority (24).
It is likely that multidisciplinary, integrated models of HCV care involving partnership
between HCV specialists and community healthcare providers (14), and the continuing
extension of HCV care into community settings, will be the appropriate foundation for HCV
services adapted to the needs of PWID. The traditional location of HCV assessment and
treatment in hospitals is a model of care ill-adapted to the needs and life circumstances of
many PWID (14). At the same time, the limited infrastructure and HCV knowledge in OST
clinics and primary care centres restrict their ability to provide HCV assessment and
treatment unsupported (14). Thus, for the foreseeable future, a multidisciplinary, partnership
approach is likely to be important. Various integrated care models have been demonstrated to
successfully enhance HCV assessment and interferon-based treatment of PWID, including
telemedicine clinics between specialists and primary care providers (25), and on-site HCV
nursing and specialist support within OST clinics and community health centres (23, 26).
The epidemiological, demographic and socio-political situation with regard to HCV varies
across Europe and there is diversity in countries programmatic responses to the epidemic
(21). Comprehension of such issues and collaboration between key organisations and member
states will be important for any chance of eliminating HCV (21). The relatively free
movement of people between member states means that interventions will have greater
effectiveness if countries work together and coordinate their activities. Collaboration and the
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pooling of intellectual, research and political resources will hasten learnings regarding
optimum HCV service provision.
Hepcare Europe is an EU-supported project involving collaboration between five institutions
across four member states, including: University College Dublin (UCD), Ireland; Servicio
Andaluz De Salud (SAS), Spain; Spitalul Clinic de Boli Infectioase si Tropicale “Dr. Victor
Babes” (SVB), Romania; and University of Bristol (UoB) and University College London
(UCL) in the United Kingdom. The project aims to develop, implement and evaluate
interventions to improve HCV diagnosis, evaluation and treatment among PWID and linked
groups such as prisoners and the homeless, across a range of settings in Dublin, Seville,
Bucharest and London. We will develop outreach and integrated models of HCV care in the
participating sites that are tailored to their health service infrastructure and population needs,
to improve PWID engagement and retention along the cascade of HCV care. Interventions
will include point-of-care diagnostics, nurse outreach, community-based evaluation of HCV
disease, patient and healthcare professional education, and peer support. We will evaluate the
feasibility, acceptability, potential efficacy and cost-effectiveness of the interventions within
the different settings in order to provide a better understanding of how improvements to the
care of PWID can be achieved.
1.1 Specific Objectives include:
Primary objectives
To determine the feasibility, acceptability and potential efficacy of the various
components of the Hepcare Europe package of interventions across the different
settings to enhance HCV identification, evaluation and treatment among PWID and
linked groups. Feasibility will be determined by examining the uptake of the
10
interventions across the different settings. Acceptability will be determined by
examining participants’ experiences of and satisfaction with the interventions.
Potential efficacy will be assessed by examining the number and proportion of
participants diagnosed, evaluated, treated, and attained SVR, pre- and post-
intervention.
Secondary objectives
To determine how the cost-effectiveness of the interventions might vary across
different EU settings, and use the results to help guide decision criteria for when
specific case-finding and care strategies should be used;
To engage with key stakeholders, nationally and in Europe, to ensure our findings
contribute to HCV policy and practice.
2. CONTEXT AND METHOD
2.1 Study Design and Settings
Hepcare Europe is a service innovation project and a prospective, observational, mixed-
methods, pre-post intervention study.
Fieldwork in relation to the Hepcare interventions will take place in four sites (Dublin,
London, Seville and Bucharest) and a health economics analysis will be conducted in the fifth
site (Bristol). Taken together, participating sites have different histories and policies in
relation to opioid substitution treatment (OST), harm reduction and access to the new HCV
therapies and have different models of primary care (Table 1).
Dublin, Ireland
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Estimates suggest 20,000-30,000 people in Ireland are chronically infected with HCV (27).
Injecting drug use is the main risk factor in 80% of HCV cases (28). Studies indicate a
prevalence of HCV antibodies (anti-HCV) among PWID of 62-81% (29-32). According to a
recent study, between the years 1991-2014, an estimated 12,423 of approximately 16,400
PWIDs have been infected with HCV, with 9,317 chronically infected (27).
Methadone is the only form of OST prescribed in Ireland and is provided by addiction
treatment centres, specialised GPs and in prisons (33). Ireland has three models of needle and
syringe programmes (NSP), including: fixed site facilities, outreach syringe provision and
pharmacy-based programmes (34).
National HCV screening guidelines have recently been published (35) identifying risk groups
for screening, including PWID and linked groups such as prisoners and homeless people. The
guidelines highlight that novel strategies and/or extra support may be required to engage
prisoners and homeless people with screening and to enable their linkage to specialist HCV
care and treatment. A National Hepatitis C Treatment Programme oversees access to DAA
treatments on a phased basis. Until 2017, access was organised according to clinical need and
restricted to those who were infected with HCV through blood and blood-products and those
scoring >8.5 kPa on FibroScan. In early 2017 the criteria were revised to remove this
threshold, but a limited healthcare budget and the high cost of DAAs continue to restrict the
numbers who can avail of treatment.
The Hepcare Study in Dublin is taking place in two settings: (i) a closed, medium-security
prison for adult males located in the centre of Dublin, which has the largest prison population
in Ireland; and (ii) OST-prescribing GP practices in North Dublin. Both settings are within
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the catchment area of the participating centre in Ireland, i.e. the Mater Misericordiae
University Hospital, an academic teaching hospital in Dublin’s North Inner City. The
hospital’s Infectious Diseases Department cares for a large number of patients with HIV
and/or HCV.
London, UK
Estimates suggest approximately 214,000 people are living with CHC in the UK (36).
Injecting drug use is the risk factor in 90% of HCV cases (37). Around half of PWID are
thought to be anti-HCV positive in England (52%) and Wales (53%), with levels being lower
in Northern Ireland (23%) and higher in Scotland (58%) (36).
In the UK, options for OST include methadone, buprenorphine, and rarely diamorphine. OST
is delivered through specialist outpatient drug treatment services and shared care
arrangements with GPs. NSP are provided mainly through pharmacies and drug treatment
services, but also via street outreach workers and mobile van units (37). According to Public
Health England’s “Shooting Up” report, trends in injecting drug use in the UK are changing,
with a growing number of people injecting amphetamines and amphetamine-type drugs such
as mephedrone (38). There has been a recent sharp increase in HIV and HCV infections in
South-West Wales linked to a move from opiate injecting toward injecting newly emerged
drugs such as mephedrone (39). A HIV outbreak among PWID in Glasgow was also reported
in 2015 (38).
In England, access to DAA treatments is organised by 22 Operational Delivery Networks
who provide clinical leadership over a given geography and are responsible for delivering
HCV treatment under certain conditions. NHS guidance in 2015 was that those with
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Genotype 1 and cirrhosis, and those with decompensated cirrhosis (any genotype) were
eligible for treatment with the new oral drugs (40). Eligibility criteria have since been relaxed
and currently all genotypes regarding of stage of fibrosis are eligible for DAAs (41).
The Hepcare Study in London is taking place in two settings: (i) using the resources and
Mobile Health Unit of the “Find&Treat” homeless health team of University College London
NHS Trust, Hepcare will conduct outreach to selected sites within underserved communities
in metropolitan London. Sites to be visited by the mobile van and/or screening staff will
include homeless residential hostels, day centres and drug services; and (ii) OST-prescribing
GP practices.
Bucharest, Romania
Approximately 489,000 people are estimated to have CHC in Romania (42). The majority of
cases were infected nosocomially before 1990 (42). However, in the last decade there has
been an increasing trend of HCV infections among PWID, with seroprevalence rates among
PWID mounting from 47.6% in 2004 to 82.4% in 2012 (43).
HIV and Hepatitis B (HBV) infection among PWID also represent a challenge for the
healthcare system. Rates of HIV and HBV were low among PWID until 2011, when an
explosive increase in blood borne virus infections in drug users was reported, with HIV
prevalence among PWID rising from 4.1% in 2010 to 49.2% in 2013, and HBV prevalence
from 13.1% to 27.7% in the same period (44). This increase was driven by the replacement of
heroin with new psychoactive substances called “ethnobotanicals”, which have amphetamine-
like effects, cause a high addiction and need for multiple administrations per day. This
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change in injecting trends coincided with reduced funding of NSP and consequent shortage of
clean needles (43, 45).
In Romania, OST (methadone, buprenorphine, or combination buprenorphine/naloxone) is
delivered mainly through public medical units and Drug Prevention, Evaluation and
Counselling Centres in Bucharest, as well as in prisons. One NGO and three private providers
also provide OST. Coverage is considered low however, with an estimated 1 (<1-1) OST
recipient per 100 PWID (46). NSP are provided by NGOs in Bucharest and two adjacent
counties through outreach programmes in fixed locations and via street workers and a mobile
team. Most injecting drug use is centred in Bucharest, where according to the latest reported
data from 2013, there were an estimated 6288 PWID (43).
In 2014, supported by Norwegian Funds, a national project was initiated to create a national
hepatitis registry. Secondary objectives of the project include testing for HIV and hepatitis in
vulnerable groups, improving access to medical services and NSP for PWID, providing HCV
education and training for healthcare professionals, and increasing public awareness of HCV,
HBV and HIV.
Access to interferon (IFN)-free therapies is restricted in Romania. In 2015-2016, 5000
patients with compensated cirrhosis were treated with IFN-free regimens, while non-cirrhotic
patients were eligible for IFN-based therapies only. Access was expanded in 2017 to
decompensated cirrhotic patients, non-cirrhotic F3 patients, non-cirrhotic F2 patients with a
contraindication to IFN-treatment, F2 patients with cryoglobulinemia, liver transplant
recipients with recurrence of HCV, dialysis patients (F2-F4) and medical staff (47). In
addition to restrictions relating to stage of fibrosis, patients with HIV/HCV co-infection are
15
required to give a negative drug test to receive reimbursed DAA therapy. However, those
mono-infected with HCV do not seem to have the same requirement (41).
The Hepcare Study in Bucharest is taking place in a range of settings, including: (i) night
shelters and NGOs caring for homeless people; (ii) OST centres; (iii) an inpatient drug
treatment unit; and (iv) prisons. Patients from these sites will be referred to the participating
center in Romania, i.e. the Victor Babes Clinical Hospital for Infectious and Tropical
Diseases. The hospital serves a catchment of 50% of the Bucharest region and six additional
surrounding districts and has been a centre for HIV / AIDS since 1989 (a University hospital
since 1976).
Seville, Spain
Approximately 472,000 adults are estimated to have CHC in Spain (48). Over 300,000
individuals in Spain have a lifetime history of injecting drugs and estimates of HCV
prevalence among PWID are 60-80% (49).
In Spain, OST (methadone or buprenorphine/naloxone combination) is delivered mainly
through specialised outpatient drug treatment centres, some primary care centres, inpatient
facilities and prisons. Harm reduction services are provided through social emergency
centres, mobile units, pharmacies and prisons. Most harm reduction programmes include
preventive educational interventions, NSP, BBV testing, and HAV / HBV vaccinations (50).
Spain also has 13 facilities for supervised drug consumption (50).
In 2015, a National Strategic Plan for tackling HCV was published (51), consisting of four
strategic directions:
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Establish the prevalence and epidemiology of HCV infection in Spain, promote early
diagnosis in priority populations, primary prevention of HCV infection and secondary
prevention of HCV-related complications;
Define the scientific-clinical criteria for establishing the appropriate therapeutic
strategy for CHC patients, including prioritizing those with most clinical need for
initial access to DAAs;
Establish coordination mechanisms to guarantee the implementation of the Strategy;
Foster knowledge regarding HCV prevention, diagnosis and treatment in the National
Health System.
The first strategic line of the Spanish Plan regarding early diagnosis has not been developed
because all funding has been diverted towards the second strategic line referring to HCV
treatment as a large burden of previously diagnosed infections are still pending treatment in
Spain. Priority groups identified by the Strategy for DAA treatments include: patients with
advanced liver fibrosis (F2-F4) or extra-hepatic manifestations of HCV, patients on transplant
waiting lists, liver transplant recipients with recurrence of HCV, non-liver transplant HCV
patients, and patients who have not responded to triple therapy with first generation protease
inhibitors. In June 2017, access to DAA treatment was no longer restricted to priority groups.
Currently, any HCV-infected patient can be treated with DAA combinations, regardless of
fibrosis or any other clinical situation (41).
The Hepcare Study in Seville is taking place in a number of settings in the province of
Seville, corresponding to the area of the participating center in Spain (i.e. the Hospital
Universitario de Valme), including: (i) NGOs and other organisations dedicated to homeless
people; (ii) drug addiction units; (iii) therapeutic communities; and (iv) OST prescribing
17
primary care centres. The Hospital is a tertiary care university hospital and its Infectious
Diseases Unit is the premiere unit in the region.
2.2 Study populations, sampling and recruitment
The project is focused on three target groups:
(i) PWID at-risk of or diagnosed with HCV, and linked groups such as people who
are homeless, sex-workers, and prisoners;
(ii) Healthcare providers working with the aforementioned groups, including: GPs,
Practice Nurses, Counsellors, Social Workers and Outreach workers; and
(iii) Organisations involved in influencing health systems, including: national patient
support groups, national bodies in participating countries, and key European and
international bodies.
Population, convenience or purposive sampling will be conducted depending on the aims of
the work package and setting.
2.3 Hepcare Work Packages
Hepcare Europe includes the following inter-connected work packages (WPs) (see Figure 1
and Table 2):
2.3.1 HepCheck
This WP will develop, implement and evaluate interventions to enhance HCV screening of
PWID and linked groups, who although at risk for and often infected with HCV, are
frequently marginalized in their engagement with health services. HepCheck will outreach
screening to these groups through their points of contact with services in the community (e.g.
18
OST clinics, homeless services, prisons) and use a point-of-care testing strategy. A meta-
analysis comparing HCV POCTs with reference tests found that on pooled analysis POCTs
were highly accurate for diagnosing HCV, although authors cautioned care in the choice of
test as the sensitivity and specificity of individual tests varied widely (52). HepCheck will use
the OraSure Technologies OraQuick HCV rapid antibody test which samples oral/salivary
fluid and avoids the need for phlebotomy. According to a field study, the sensitivity of the
test was 97.8% and specificity 100% (53).
Individuals attending participating services in the four sites (Dublin, London, Bucharest,
Seville) will be offered HCV screening using the OraQuick test. Those who accept the
screening offer and test antibody positive (Ab+), and individuals who indicate they have
already been diagnosed with HCV but have not received or engaged with specialist follow-
up, will be offered further evaluation for HCV, including: HCV polymerase chain reaction
(PCR) and antigen test to determine whether they have chronic infection, FibroScan to assess
the extent of liver disease, and referral for HCV treatment if eligible. Individuals once
referred to specialist hepatology/infectious diseases services will be assessed as to their
suitability for HCV treatment and any barriers to treatment will be identified. The original
service from which participants were recruited, with the involvement of allied health
professionals, can develop a care plan to address the issues preventing treatment. HepCheck
will thus address engagement with HCV evaluation and treatment as well as screening, by
using the POCT offer as the entry point into the cascade of care required to be cured of HCV.
A minimum of 2,000 individuals will be screened for HCV across the four sites. We will
evaluate the feasibility, acceptability and potential efficacy of the screening interventions for
individuals attending homeless and other services in the partner sites, including establishing
19
the utility of POCT with HCV oral tests in diverse populations and different
countries/settings. A quantitative audit of access to HCV treatment and of treatment
outcomes in HCV-infected individuals identified during the screening process will be
conducted. Qualitative interviews with a purposive sample of participants will examine
acceptability of the interventions and barriers and facilitators to HCV treatment completion.
2.3.2 HepLink
This WP will develop, implement and evaluate a complex intervention to improve linkage to
HCV evaluation and treatment among OST patients attending general practice and
specialised OST centers. In many EU countries, including Ireland, Spain and the UK, general
practice is increasingly involved in providing OST and continuing care for PWID. It is thus a
key setting to target to address HCV-related morbidity and mortality among PWID. In
Romania, OST is not prescribed by GPs but is provided through specialised centers. GPs and
other OST prescribers often have long-standing relationships with their OST patients and as
such can facilitate access to HCV evaluation and treatment among PWID where shared care
partnerships with secondary/tertiary providers are developed.
HepLink will outreach a HCV-trained liaison nurse into GP practices and OST centers to
optimise interaction and integration between primary and secondary care. S/he will conduct
on-site specialist evaluation of HCV disease (including FibroScan) in the general practice /
OST center setting, and assist in referring HCV-infected patients to a hepatology/Infectious
Diseases service for HCV treatment. S/he will educate OST providers, GPs, practice staff and
patients on HCV and developments in its diagnosis and treatment and ensure that patients’
HCV testing and other blood borne virus screening and vaccinations are up-to-date. Research
20
has shown that practitioner education and nurse liaison can increase rates of HCV screening
and linkage to specialist care in general practice (54).
A central component of the intervention will be the staging of liver fibrosis among HCV-
infected patients using a FibroScan. Studies have shown the FibroScan to be equivalent to
liver biopsy, although obesity, female sex, operator experience, and age older than 52 may
give invalid results (55, 56). Currently, in many HCV treatment guidelines, a FibroScan is
used to determine eligibility for state-supported HCV treatment utilizing DAA therapies.
Thus the FibroScan has become an essential component of the evaluation of patients with
HCV.
Twenty-four OST-prescribing GP practices and OST centers and 240 patients will be
recruited across the four participating sites. In addition to developing and delivering the
complex intervention, we will evaluate the intervention’s feasibility, acceptability and likely
efficacy within the different countries / health systems. An audit of patients’ clinical records
will be conducted at baseline and 6-months post-intervention to examine HCV care processes
and outcomes following the intervention. Qualitative interviews with a purposive sample of
OST providers and patients will assess the intervention’s acceptability.
2.3.3 HepFriend
This WP will develop and implement peer support interventions to enhance engagement with
HCV screening, assessment and treatment within the HepCheck and HepLink WPs. Peers are
individuals with similar life or disease experiences to the clients they are supporting, i.e.
HCV infection / drug misuse / homelessness. We will recruit, train and support peers to
21
improve HCV care integration between community and specialist services following the
development of the HepCheck and HepLink interventions.
Peers will be trained to assist the clinical teams in HepCheck and HepLink with POCT,
FibroScanning, and conducting pre-treatment assessments. They will receive training in how
to support people through the HCV cascade of care, including those who are eligible for or
undergoing HCV treatment. Peers will support clients by giving advice and education around
the care pathway, accompanying clients to clinical appointments if desired, reminding clients
of appointments, and meeting clients for social support. HepFriend will be conducted at all
four sites.
We will determine the feasibility, acceptability and potential efficacy of the peer support
interventions combined with HepCheck and HepLink, to improve HCV case detection and
treatment uptake and outcomes in the diverse populations and different countries/settings.
The client and peer experience of peer support will be assessed by qualitative interviews.
2.3.4 HepEd
There have been a number of developments in HCV diagnostics and treatment in recent
years. However, a cultural lag has been identified between such developments and societal
understandings of them (57). This WP will develop and deliver educational interventions to
prepare affected communities for HCV testing, assessment and treatment and to prepare
healthcare providers to act as partners in a shared care primary/secondary partnership for
treatment of HCV. These interventions will be utilised within the other WPs of the project,
i.e. HepCheck, HepLink and HepFriend.
22
HepEd will:
Develop and implement a programme of multidisciplinary, inter-professional
education on HCV for healthcare providers. This will include the hosting of
Masterclasses on HCV and advances in its diagnosis and treatment for a
minimum of 30 healthcare providers at each of the four sites (i.e. 120
providers in total) and the development of video and online resources to reach
a wider audience.
Develop and/or adapt educational materials for use in affected communities,
including PWIDs. This will include educational materials to prevent those
who test negative from subsequently acquiring HCV.
Develop and adapt training materials for peers (i.e. HepFriend).
To evaluate the impact of the HCV masterclasses, attendees will be asked to complete pre-
and post-intervention questionnaires on their experience of the masterclass and the extent to
which they found it of value in providing HCV care for patients.
2.3.5 HepCost
This WP will evaluate the cost-effectiveness of the various Hepcare interventions in the
different countries / settings and use the results to help guide decision criteria for when
specific case-finding and care strategies should be used. The four interventions to be
evaluated are HepCheck, HepLink, HepFriend and HepEd.
An existing dynamic compartmental model of HCV disease progression, screening, treatment
and transmission among PWID and non or ex-PWID will be adapted to evaluate the Hepcare
interventions. The model will initially be parameterised to evaluate each intervention in a
23
specific setting, and then adapted to consider the other settings. One setting will be modelled
as a base case for each intervention and then the other settings will be modelled as a
sensitivity analysis based on that primary setting. We will perform extensive sensitivity
analysis to explore thresholds of cost-effectiveness in terms of minimum levels of
intervention effect or testing yield, as well as what key factors and changes to the intervention
may increase or decrease cost-effectiveness.
2.3.6 Dissemination
This WP aims to maximise the dissemination of findings from the project and its impact on
HCV policy and practice nationally and in Europe. In addition to disseminating findings to
healthcare professionals, affected communities, and the scientific community through
conferences, peer-reviewed publications and social media, we will proactively engage with
key stakeholders and policy-makers, nationally and in the EU, including service-user
organizations, NGOs, key people responsible for national HCV policy at each site, and EU
HCV and drug policy agencies.
2.3.7 Evaluation
This WP will evaluate how the project is addressing its overarching objectives and will
consist of an external review by an approved agency with experience in evaluating EU level
grants, in addition to regular internal reviews by the Project Steering Group.
2.5 Data generation and outcome measures
Several key outcome measures relating to the cascade of HCV care pre- and post-intervention
will be examined in all WPs and settings, including: number and proportion of participants
tested for HCV infection; number and proportion who are HCV positive; number and
24
proportion of HCV-positive patients who are: FibroScanned; referred to specialist care;
attended specialist care; initiated HCV treatment; completed HCV treatment; achieved SVR;
and number and proportion of deaths. Data will be generated through review of patients’
clinical records and through questionnaires and interviews with patients and healthcare
providers.
To facilitate clinical and research follow-up of participants, individuals contact details as well
as the contact details of their GP and other support services will be collected at recruitment to
the study. Follow-up data on access to and retention in HCV care (e.g. engagement with
specialist services, treatment completion etc) will be collected by the research team from the
participants’ health records and/or from follow-up questionnaires with participants. In the
latter case, members of the research team will contact participants directly or via their support
service/care team.
Data on participants alcohol and drug use will be collected as part of the HepCheck and
HepLink WPs and will form part of the patient referral information that is forwarded to
hepatology/infectious diseases services. Detailed data on previous and current drug use
(including drugs used, mode of administration, and frequency of use) will be collected as part
of HepCheck and will enable an analysis of the potential associations between psychoactive
substances use and HCV treatment outcomes.
2.5.1 Health Economics
Cost-effectiveness results will be expressed in terms of incremental cost of effectiveness
ratios (ICERS) for each of the interventions, country-specific. The costs for each intervention
will be estimated for each country/setting, including staff time spent on the intervention and
25
any relevant training and equipment costs. Treatment and care costs will be estimated
following discussions with health care providers in each setting, and applying or adapting
available costs from their or other EU settings. This will include costs for individuals that
commence HCV treatment and those that do not. Health care benefits will be estimated in
terms of quality adjusted life years saved (QALYS) with existing health utility data being
used for different HCV disease stages.
2.6 Ethical Considerations and Project Governance
Ethical approval for the project has been received from our respective institutional review
boards in the four fieldwork settings (i.e. Mater Misericordiae University Hospital, Dublin;
Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest; Hospital
Universitario de Valme, Seville; North West - Haydock Research Ethics Committee,
London).
The project governance structure includes: (i) an International Advisory Board, composed of
academics, clinicians, researchers, and representatives from relevant EU regulatory bodies
and service-user organisations, to provide external oversight; (ii) a Project Steering Group,
composed of WP leaders and site leaders, to provide internal oversight; and (iii) site-specific
Project Management Teams to execute the project at each site.
3. DISCUSSION
We have described the focus of the Hepcare Europe project which is to develop, implement
and evaluate interventions to enhance diagnosis, evaluation and treatment of HCV among
PWID. PWID at risk of or infected with HCV often have complex needs. Many are unaware
of their infection and those diagnosed often do not access specialist care. Recent
26
developments making HCV testing and evaluation more portable, less invasive and less
reliant on specialists, enhance opportunities for further extension of HCV care to community
settings to reach more patients. Hepcare Europe will design and evaluate outreach
interventions to PWID and linked groups such as the homeless, through their points of
contact with services in the community, e.g. prison, addiction services, primary care, hostels,
and NGOs, in four European sites. Interventions will focus on enhancing HCV testing and
evaluation of HCV disease in the community through education, point-of-care diagnostics,
nurse outreach, and peer support, and will create shared care partnerships between
secondary/tertiary and primary/community care to facilitate diagnosed patients to access
treatment with the recently available DAAs. We will evaluate the feasibility, acceptability,
potential efficacy, and cost-effectiveness of the interventions to improve HCV care processes
and outcomes for PWID in a variety of settings in the four sites.
While the Hepcare package of interventions aim to facilitate access to HCV treatment, the
interventions will not change treatment eligibility criteria/recommendations. Decisions
regarding HCV treatment of individual participants (i.e. treatment eligibility and treatment
regimen) will be made by clinicians within the specialist hepatology/infectious diseases
services to which HCV-infected participants are referred, and will be based on each
region/country’s own national guidelines and policies.
We have created a consortium of researchers and clinicians active in HCV care in Ireland,
UK, Spain and Romania to support mutual learning and implementation of interventions
across sites. The geography and history of the sites reflect the epidemiological and
demographic diversity in risk populations and diversity in socio-economic and political
environments across Europe. Sites vary in the structure of their health systems, models of
27
primary care, and policies around OST provision, harm reduction and access to the new DAA
therapies. The UK, for example, has a well-developed social welfare programme and free
health care through the National Health System. Ireland has a different model of care, with
private and public health provision. Spain similarly has a private/public partnership in the
provision of medical care and economic restrictions at present on its health care budget.
Romania, as one of the newer members of the EU, still has some barriers in its systems of
care. The logistics of developing integrated models of HCV care will differ across sites given
their heterogeneity. Through our work and partnership, we will interrogate the issues, from
testing to treatment, to implement new models of care that are adapted to the needs of PWID.
To our knowledge, Hepcare Europe is the first multi-country European feasibility study
examining interventions targeting all points in the HCV cascade of care from case-finding to
treatment in diverse populations of PWID in a range of settings and countries. Other
initiatives, such as The Extension for Community Healthcare Outcomes (ECHO) project (25,
58), The Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS)
study (23, 26), The Hepatitis C Assessment and Testing (HepCAT) project (59-61), and The
Hepatitis C: Assessment through to Treatment (HepCATT) study (62, 63), and more recent
studies in the Netherlands (64), Ukraine (65) and Scotland (66) are based in single countries
or outside Europe, are focused on particular points in the HCV cascade of care (e.g. testing
and referral or evaluation and treatment), and do not include the broad range of settings that
Hepcare will. We hope that Hepcare with its breadth and scope will complement these more
focused studies.
3.1 Methodological considerations
28
As a pre-post feasibility study using mixed methods (mathematical modelling, qualitative
data, cross-sectional, and longitudinal cohort elements), Hepcare does not employ a
controlled trial design and lacks the scientific rigour of a RCT which could definitively
determine effectiveness of the interventions. Also, as Hepcare interventions will be tailored
according to the service infrastructure and population needs at each site, the implementation
of interventions will not be homogenous.
However, this is a real world service innovation project that aims to design and deliver
interventions that will meet the needs of PWID populations in a variety of settings in four
European sites. We have used the information gleaned from the literature and lessons learned
from previous studies to generate a programme of work which we propose will deliver
evidence-based interventions (i.e. POCT, FibroScan, nurse liaison) though means and
modalities that will be convenient and adapted to the needs of PWID.
Analyses of the Hepcare data will indicate which components of the Hepcare package of
interventions work well and which don’t in different real world settings and populations. This
will allow further refinement of the interventions. Cross-sectional analyses of the data will
provide insights into the uptake of the interventions, while longitudinal data will provide
information on the potential impact of the interventions over time, including the throughput
of participants in the cascade of HCV care. Qualitative data will provide insights into the
acceptability of the interventions to service-providers and service-users. Health economic
analyses will indicate the cost-effectiveness of the interventions and how this may vary in
different settings.
29
One possible threat to our study is the effect on efficacy outcome measures of the continuing
evolution of national HCV treatment strategies and treatment eligibility criteria within each
country, which will impact study outcome measures such as HCV treatment uptake and SVR,
and may have knock-on effects on measures such as referral and attendance at specialist
services. At the same time, this evolution provides opportunities for Hepcare Europe to
influence the direction of national HCV strategies through its pro-active engagement with
policy-makers.
3.2 Implications for research, education, practice and policy
As a service innovation project involving PWID populations in a variety of settings in four
European sites, lessons learned from the project will provide real world contributions to
implementation science regarding community-based interventions for HCV infection among
PWID and linked groups. This may also inform the design of subsequent RCTs in this area.
The findings from this feasibility study may inform integrated care research more broadly,
particularly for marginalised groups.
The interventions being developed as part of Hepcare have the potential to make an important
impact on patient care through providing quality healthcare to marginalised populations who
might otherwise go undiagnosed and untreated.
The development of online educational materials will create a continuing resource for
patients and healthcare professionals across Europe and may inform educational interventions
for the aforementioned groups, in particular ensuring these are applicable for an international
audience.
30
Lessons learned from the study can be incorporated into national and European guidelines
and strategies for HCV. Consortium members are actively engaged with key stakeholders and
policy-makers locally and nationally to ensure that Hepcare addresses key issues in their
region/country and contributes to improved policy and practice. Preliminary learnings from
the project have already informed national HCV screening guidelines in Ireland (35).
3.3 Conclusions
HCV infection is highly prevalent among PWID. Yet many PWID are unaware of their
infection and few have received HCV treatment. The burden of HCV-related liver disease is
growing and is expected to increase substantially in the next decade. The potential of the new
HCV therapies to address this burden and to achieve the reductions in HCV-related mortality
set out in the WHO GHSS will only be realised if the identification of HCV among PWID
and linkage to care and treatment of those who are chronically infected is optimised.
Taken together, our research findings will determine the feasibility, acceptability, likely
efficacy, and cost-effectiveness of new models of care for engaging and retaining PWID in
the cascade of HCV care. The analyses conducted as part of Hepcare Europe will be key in
highlighting evidence for a scaled-up integrated care strategy for HCV infection in
participating countries and in Europe.
Key Issues
Hepatitis C (HCV) infection is associated with liver cirrhosis and hepatocellular
carcinoma, and is highly prevalent among people who inject drugs (PWID).
Many PWID are unaware of their infection and few have received HCV treatment.
31
The burden of HCV-related liver disease among PWID will substantially increase in
the next decade.
Developments in HCV treatment have increased cure rates to >90%, in addition to
shortening treatment times and improving safety profiles.
As many PWID remain unaware of their infection and/or are not accessing HCV care,
it is evident that new strategies to reach such individuals are necessary, including new
testing strategies to increase the number diagnosed, and improved care pathways to
ensure those diagnosed are successfully linked to HCV evaluation and treatment.
Hepcare Europe is an EU-supported, service innovation project, involving
collaboration between five institutions across four member states (Ireland, UK, Spain,
Romania). The project aims to develop, implement and evaluate interventions to
improve HCV identification, evaluation and treatment among PWID and linked
groups such as the homeless and prisoners through their points of contact with
services in the community in Dublin, London, Seville and Bucharest.
The geography and history of the four sites reflect the epidemiological and
demographic diversity in risk populations and diversity in socio-economic and
political environments across Europe.
Interventions will be tailored to the health service infrastructure and population needs
at each site and will incorporate point-of-care-diagnostics, nurse outreach,
community-based evaluation of HCV disease, health provider and patient education,
peer support, and the development of integrated models of HCV care.
We will evaluate the feasibility, acceptability, potential efficacy and cost-
effectiveness of these interventions to get a better understanding of how
improvements to the care of PWID can be achieved.
32
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
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36
Table 1: HCV infection in the general population, PWID population and coverage of
harm reduction measures in Hepcare Europe countries
Countries CHC in
general
population
HCV
prevalence
among PWID
OST:
Forms
provided
aOST:
Coverage*
aNSP:
Coverage†
Ireland 20,000-
30,000
62-81% Methadone
High: GTP (93-
GTP)
Low: 46 (37-62)
UK 214,000 52% Methadone,
Buprenorphine,
Diamorphine
England
High: 67 (62-72)
Scotland
Moderate: 23
(21-27)
Wales: NC
Northern
Ireland: NC
England: NE
Scotland
High: 277 (249-
321)
Wales: NC
Northern Ireland:
NC
Romania 489,000 82.4% Methadone,
Buprenorphine,
Combination
Buprenorphine/
Naloxone
Low: 1 (<1-1) Low: 18 (13-24)
Spain 472,000 60-80% Methadone,
Combination
Buprenorphine/
Naloxone
High: GTP Moderate:141
(84-428)
CHC: Chronic Hepatitis C; HCV: Hepatitis C Virus; OST: Opioid Substitution Treatment;
NSP: Needle and syringe programmes; GTP – estimate greater than parity; NC: intervention
exists and data on the extent of service provision were identified for this country, but no
estimate of the prevalence of injecting drug use has been located for this country;
NE: intervention exists in that country, but no data on the extent of service provision were
located;
*Number of OST clients per 100 PWID; †Number of needle-syringes distributed per PWID
per year a (Larney, Peacock et al. 2017) (46)
37
Figure 1: Hepcare Europe Work Packages
Primary Care
Secondary care
WP4: HepCheck (screening)
WP5: HepLink (linkage to care)
WP 7: HepFriend (peer advocacy
support)
WP 6: HepED (inter-professional
education)
WP8: HepCost
WP 1 Coordination; WP 2 Dissemination; WP3 Evaluation
38
Table 2: Hepcare Europe Work Packages: Study populations, interventions,
comparisons and key outcomes (PICO)
Work
Package
Population Intervention Comparison Outcomes
HepCheck Prisoners
(Dublin)
Homeless;
PWID
(Bucharest)
Underserved
communities
(London)
Homeless;
PWUD
(Spain)
(Target: screening
2000 individuals at-
risk of HCV across
4 participating sites)
Outreach and
point of care
testing of at-
risk populations
Pre-post
intervention
N individuals screened
for HCV
N new cases of HCV
detected
N HCV-positive
participants:
FibroScanned
Referred to
hepatology/ID
Attended
hepatology/ID
Started HCV
treatment
Completed HCV
treatment
Attained SVR
HepLink Patients on
OST in GP
practices /
OST Centers
Target : 24
practices/centers
and 240 patients
across 4
participating sites
Outreach of a
HCV-trained
nurse into GP
practices/OST
centers to
provide HCV
education,
community-
based
evaluation of
HCV disease,
and assist with
referral to
specialist care
Pre-post
intervention
N participants screened
for HCV
N participants HCV
positive
N HCV-positive
participants:
FibroScanned
Referred to
hepatology/ID
Attended
hepatology/ID
Started HCV
treatment
Completed HCV
treatment
Attained SVR
39
PWID: People who inject drugs; PWUD: People who use drugs; HCV: Hepatitis C Virus; ID:
Infectious Diseases; SVR: Sustained Virologic Response
HepEd Healthcare
professionals
(all sites)
Patients (all
sites)
Peers (all
sites)
Development
of educational
resources for
health care
providers,
patients and
peers
Pre-post
masterclass
survey
Improvements in HCV
knowledge
HepFriend Underserved
communities
(London)
Patients on
OST/PWID
(Seville)
Prisoners
(Dublin)
Homeless
(Bucharest)
Peer support
system to assist
at-risk groups
to engage with
screening,
assessment and
treatment
within
HepCheck and
HepLink
Pre-post
intervention
N participants screened
for HCV
N HCV-positive
participants:
FibroScanned
Referred to
hepatology/ID
Attended
hepatology/ID
Started HCV
treatment
Completed HCV
treatment
Attained SVR